Open AccessSynthesis and Characterization of Transition-State Analogue Inhibitors against Human DNA Methyltransferase 1
Author(s) -
Farah Lamiable-Oulaidi,
R.K. Harijan,
Karl J. Shaffer,
Douglas R Crump,
Yan Sun,
Quan Du,
Shivali A. Gulab,
Ashna A. Khan,
Andreas Luxenburger,
Anthony D. Woolhouse,
Simone Sidoli,
Peter C. Tyler,
Vern L. Schramm
Publication year - 2022
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c01869
Subject(s) - dnmt1 , dna methyltransferase , chemistry , methyltransferase , dna methylation , methylation , cpg site , dna , biochemistry , transition (genetics) , gene , gene expression
Hypermethylation of CpG regions by human DNA methyltransferase 1 (DNMT1) silences tumor-suppression genes, and inhibition of DNMT1 can reactivate silenced genes. The 5-azacytidines are approved inhibitors of DNMT1, but their mutagenic mechanism limits their utility. A synthon approach from the analogues of S -adenosylhomocysteine, methionine, and deoxycytidine recapitulated the chemical features of the DNMT1 transition state in the synthesis of 16 chemically stable transition-state mimics. Inhibitors causing both full and partial inhibition of purified DNMT1 were characterized. The inhibitors show modest selectivity for DNMT1 versus DNMT3b. Active-site docking predicts inhibitor interactions with S -adenosyl-l-methionine and deoxycytidine regions of the catalytic site, validated by direct binding analysis. Inhibitor action with purified DNMT1 is not reflected in cultured cells. A partial inhibitor activated cellular DNA methylation, and a full inhibitor had no effect on cellular DNA methylation. These compounds provide chemical access to a new family of noncovalent DNMT chemical scaffolds for use in DNA methyltransferases.